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Anesth Analg 1999;88:939
© 1999 International Anesthesia Research Society

GENERAL ARTICLES

The Effect of Tenoxicam on Intraperitoneal Adhesions and Prostaglandin E2 Levels in Mice

Bilge Celebioglu, MD*, Nima Ramzi Eslambouli, MD*, Ekmel Olcay, MD{dagger}, and Safak Atakan, MD{ddagger}

*Department of Anesthesiology, School of Medicine, Hacettepe University; {dagger}Department of Pharmacology, Hifsizsihha Institution; and {ddagger}Department of Pathology, School of Medicine, Ankara University, Ankara, Turkey

Address correspondence and reprint requests to Bilge Celebioglu, MD, Department of Anesthesiology, Çatal sokak 12/4 Maltepe 06570, Ankara, Turkey.


   Abstract
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We determined whether tenoxicam administered intraperitoneally in the preoperative period had an effect on the development of postoperative intraabdominal adhesions (IAA). For this purpose, 100 albino mice were divided into four random groups. Mice in Group 1 were given only 1 mL of 0.9% NaCl intraperitoneally, whereas in Group 2, 1 mL of tenoxicam (150 µg = 5 mg/kg) was administered. After the induction of anesthesia, a median laparotomy was performed, and the bowels were traumatized by touching them with powdered gloves before the incision was closed in Groups 3 and 4. Intraperitoneal tenoxicam was administered to mice in Group 4 after skin closure. All mice were killed after 14 days to determine macroscopic and microscopic IAA; prostaglandin E2 levels were also measured. Postoperative evaluation revealed a reduced IAA formation and a parallel decrease in tissue prostaglandin E2 levels in Group 1 and 2 mice. We conclude that intraperitoneal tenoxicam decreased IAA formation with no peritoneal reaction in the postoperative period.

Implications: Postoperative intraabdominal adhesions can cause intestinal obstruction, pelvic pain, or infertility. In this study, we showed that intraperitoneally administered tenoxicam decreases tissue prostaglandin E2 levels and intraabdominal adhesions in mice.


   Introduction
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Intraabdominal adhesions (IAA) are a common complication after abdominal surgery. Postoperative IAA can cause intestinal obstruction, pelvic pain, or infertility (1,2). Tenoxicam is an oxicam derivative and a nonsteroidal antiinflammatory drug (NSAID). Its prolonged half-life and decreased side effects have popularized its use for the relief of postoperative pain (3–7). The purpose of this study was to determine the effect of intraperitoneally administered tenoxicam on tissue prostaglandin E2 (PGE2) levels and its efficacy for reducing postoperative adhesions.


   Methods
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All animal experiments were conducted according to the guidelines set by the Hacettepe University School of Medicine, where this study was performed. One hundred albino mice of both genders with a mean ± SD weight of 30 ± 1.02 g were anesthetized with ketamine 75 mg/kg IM. Pure sterile tenoxicam powder was diluted with water to obtain a solution of 150 µg/cm3 (8,9). Tenoxicam was supplied as a micronized powder.

Mice were divided randomly into four groups. Two mice from Group 3 died during the waiting period and were excluded. Mice in Group 1 were given 1 mL of 0.9% NaCl intraperitoneally (IP) using 2-mL syringes, whereas 1 mL of tenoxicam (150 µg = 5 mg/kg) was administered IP to mice in Group 2 (Table 1).


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  		Table 1. Details of Study Groups
 
In Groups 3 and 4, mice were restrained in the supine position and anesthetized. After median laparotomy with an incision of 2 cm, the bowels were traumatized by touching them with powdered gloves. The peritoneum and skin were then closed. Tenoxicam 1 mL was administered IP only to mice in Group 4. Each group was placed in separate boxes and fed orally with a standard rat diet for 14 days.

All mice were killed by cervical dislocation on the 14th day and examined. IAA was scored according to the criteria defined by Nair et al. (10) (Table 2).


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  		Table 2. Gross Pathological Grading of Adhesionsa
 
Peritoneal specimens measuring 1 cm2 were obtained from the left half of the abdomen, not to include the incision line, and were kept in 10% formalin-fixed and paraffin-embedded tissue samples. Histologic sections of 5 µ were then stained with hematoxylin and eosin. A pathologist unaware of the groups evaluated the specimens under a light microscope and scored them as indicated in Table 3(11).


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  		Table 3. Microscopical Pathological Grading of Adhesions
 
Tenoxicam was administered IP because we also sought to determine whether tenoxicam would act as an analgesic locally, and we measured tissue PGE2 levels. The terminal 1 cm of the ileum of the mice was rinsed with 0.9% NaCl and frozen in a liquid nitrogen tank to be stored at -20°C for measurements of PGE2. Tissue samples homogenized in 1 N HCl were added to 2 mL of ethyl acetate and centrifuged for 3000 turns. The upper gas (ethyl acetate) was in another tube and then ethyl acetate was evaporated under the nitrogen gas (12).

Krebs solution ventilated with a 95% O2/5% CO2 mixture at 37°C was used to perfuse the isolated rat gastric fundus at a 7-mL/min volume. In isolated superfused rat fundus, a standard dose-response curve was observed. Specimens were rinsed with 1 mL of Krebs solution. Specimens were applied over 0.2 mL of tissue, and responses of the specimens were defined as the amount of tissue. Isometric findings were recorded (13).

Statistical evaluations of the macroscopic and microscopic findings and PGE2 levels were performed with Pearson’s {chi}2 and one-way analysis of variance tests, respectively. P < 0.05 was accepted as significant.


   Results
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Macroscopic and microscopic adhesion scores of the 98 rats are listed in Tables 4 and 5. In Group 1 (0.9% NaCl group), no macroscopic adhesions were noted. However, microscopic evaluation revealed inflammation in 11 (44%) mice. The same results were noted in Group 2 (tenoxicam group), except that inflammation was observed in 12 (48%) mice microscopically.


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  		Table 4. Distribution of Gross Pathological Adhesion Scores
 

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  		Table 5. Distribution of Microscopic Pathological Adhesion Scores
 
Excluding 1 mouse (4.3%), varying degrees of adhesion observed microscopically were also noted in 22 mice (95.7%) macroscopically. Microscopic evaluation revealed adhesion in all 23 (100%) animals (Group 3). Microscopically intensive scar formation (score = 5) was noted only in two mice in Group 3. Macroscopic adhesion of mice viscerae on the anterior abdominal wall (score = 4) was observed only in this group (Group 3).

In Group 4 (operation and tenoxicam) adhesions were not observed in 7 mice (28%). Microscopic evaluation revealed mild, low-grade adhesions in 24 mice (96%), whereas adhesions were not observed in 1 (4%) mouse.

A statistically significant difference was observed between Group 3 and Group 4 in terms of both microscopic and macroscopic findings (P < 0.05).

PGE2 levels were not statistically significant between Group 1 and Group 2 (P > 0.05). Between other groups, the difference was significant (P < 0.05) (Table 6).


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  		Table 6. PGE2 Changes
 

   Discussion
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IAA are fibrous adhesions formed between serosal surfaces as a result of an inflammatory reaction. IAA occur after abdominal operations and bacterial infections and are also caused by radiation, allergic reactions, chemical irritation, and tissue ischemia (11,14). Menzies (15) reported that IAA occur 90% of the time after abdominal operations. Surgical trauma causes an acute fibroproliferative inflammatory response, which results in tissue healing. Postoperative adhesions may also occur as a result of this process (1).

Damage to the serosal surfaces may be followed by secretion of histamine and other permeability-increasing factors from the mast cells. All these factors increase vascular permeability to cause plasma exudation into the peritoneum, which results in fibrin formation (16).

Many approaches have been suggested to prevent IAA. Using steroids and NSAIDs for the prevention of IAA at the first formation step has gained popularity (17–19). In studies performed with steroids such as dexamethasone, there was a significant decrease in adhesion formation (20). However, the risk of infection and wound healing problems due to large-dose steroid use are the major drawbacks of this treatment (21). Kapur et al. (22) reported the unsuccessful use of oxyphenbutazon for the prevention of IAA.

Tenoxicam is an NSAID from the oxicam group that also has strong antiinflammatory, analgesic, and antipyretic activities. Minimal side effects, prolonged half-life, and elimination not influenced by liver and kidney diseases have popularized its use in recent years (7,23,24). Yilmazlar et al.(1) documented decreased postoperative macroscopic adhesion formation with intraperitoneal tenoxicam use independent of dose.

In this study, tenoxicam was administered IP to prevent IAA. The absence of macroscopically and microscopically observed adhesions show that 0.9% NaCl used as a tenoxicam solvent did not cause IAA. No adhesions were observed, which demonstrates that IP tenoxicam is not an irritant. Microscopic inflammation was probably caused by the irritant effect of the injection.

Tissue PGE2 levels were significantly higher in Group 3 (operation group), which supports the role of PGE2 in IAA formation. The higher PGE2 levels and IAA formation in Group 2 are an important finding that supports the reduced PGE2 levels due to tenoxicam use, which resulted in a decreased incidence of IAA. Higher levels of PGE2 in Group 3 (operation group) compared with Group 4 (operation + tenoxicam group) may reflect decreased PGE2 levels and IAA with IP tenoxicam, but more extensive clinical and experimental studies are required to draw more definitive conclusions.

We conclude that IP tenoxicam decreases the incidence of postoperative IAA by reducing tissue PGE2 levels. In this study, the effectiveness of IP tenoxicam administered during the surgery was investigated for the management of IAA.


   Acknowledgments
 
We thank Sevim Ercan, MD, PhD; Korkut Özarkan, MD; Gül Aksoy, PhD; Birol Civelek, MD; and Roche Turkey Chemical Co. Ltd.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication January 5, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press